Physiological coolants impart a cooling and/or refreshing sensation to skin or mucous membranes and thereby improve the properties of foods, confections, cosmetics, medications, and other consumer goods.
l-Menthol is a strong, natural physiological coolant. However, in many compositions l-menthol is undesirable due to its pungent minty odor and bitter taste. At least eleven synthetic replacements for l-menthol are now commercially available and have been approved by FEMA as “GRAS” (generally recognized as safe) compositions. Examples include N-ethyl-3-p-menthane carboxamide (“WS-3,” see U.S. Pat. No. 4,150,052), 2-isopropyl-N,2,3-trimethyl butanamide (“WS-23,” U.S. Pat. No. 4,153,679), menthyl lactate (DE 2,608,226), monomenthyl glutarate (Food Technol. 55 (2001) 34), and N-ethoxycarbonylmethyl-3-p-menthane carboxamide (“WS-5,” U.S. Pat. No. 7,189,760). Commercial coolants incorporate many different functional groups, including carboxamides, esters, ethers, alcohols, diols, and heterocycles. Each has its own character, including not only cooling strength and threshold of perception, but also longevity of cooling action, taste and aftertaste, compatibility and/or synergy with other ingredients of the composition, physical state under ambient conditions, solubility, and other attributes.
Menthyl lactate (ML), normally prepared by direct esterification of lactic acid with menthol, is a widely used coolant for flavors, oral care, and cosmetics. The most common ML isomer, 1, derives from l-menthol and L(+)-lactic acid:

We recently reported (see U.S. Pat. No. 7,173,146) that the reaction of lactic acid and menthol produces not only ML but also significant amounts of higher lactoyl esters of ML, including menthyl lactoyl lactate MLL) and menthyl lactoyl lactoyl lactate (MLLL):
Although the lactoyl esters can comprise 25% or more of a direct esterification mixture, earlier processes had discarded them in the distillation process used to isolate ML. We discovered that controlled hydrolysis with aqueous base could selectively convert the lactoyl esters back to ML without also hydrolyzing ML, thereby maximizing the overall yield of ML. Cooling properties of the lactoyl esters were not investigated and went unnoticed.
Interest in new coolants is accelerating, fueled by expanding applications, a global consumer base, and demand for an array of goods with diverse properties such as taste, odor, freshness, and overall perception. Cost often limits coolant choices in applications such as chewing gum, for which significant concentrations of the coolant are needed. Regulatory factors can also be important. For instance, carboxamides are not currently acceptable food additives in Japan.
In sum, new coolants are needed, particularly ones that are made from inexpensive starting materials and are free of nitrogen-containing groups such as amides. Unfortunately, there is no way to easily predict the cooling properties of a compound from its structure, though some (see, e.g., J. Soc. Cosmet. Chem. 29 (1978) 185) have tried. Finding useful, inexpensive coolants remains mostly a matter of serendipity.